Thyroid hormones are administered orally, and their absorption from the gastrointestinal tract is variable. Absorption is increased if the drug is administered on an empty stomach. In the brain, T₄ (thyroxine) crosses the blood–brain barrier and diffuses into neurons, where it is converted into T₃ (triiodothyronine), which is the physiologically active form. The half-life of T₄ is 6 to 7 days, and that of T₃ is 1 to 2 days.

The mechanism of action for thyroid hormone effects on antidepressant efficacy is unknown. Thyroid hormone binds to intracellular receptors that regulate the transcription of a wide range of genes, including several receptors for neurotransmitters.

The major indication for thyroid hormones in psychiatry is as an adjuvant to antidepressants. There is no clear correlation between the laboratory measures of thyroid function and the response to thyroid hormone supplementation of antidepressants. If a patient has not responded to a 6-week course of antidepressants at appropriate dosages, adjuvant therapy with either lithium or a thyroid hormone is an alternative. Most clinicians use adjuvant lithium before trying a thyroid hormone. Several controlled trials have indicated that liothyronine use converts about 50 percent of antidepressant nonresponders to responders.